1. Field of the Invention
The present invention relates to limited release lingual/sublingual delivery systems for thioctic acid.
Thioctic acid is also known as lipoic acid, alpha lipoic acid, or ALA. Thioctic acid has two chiral enantiomers, R-(+)-lipoic acid (RLA) and S-(−)-lipoic acid (SLA), and a racemic mixture of the two R/S-Lipoic acids also exists. Additionally, each of these thioctic acid enantiomers exist in reduced (dihydro-lipoic acid) and oxidized forms. The limited release lingual/sublingual delivery system of this disclosure is effective for any and all of the above thioctic acid variants. The term thioctic acid refers to all of these various species of lipoic acid, unless specifically referred to otherwise.
2. Description of the Related Art
Thioctic acid is believed to be beneficial in several applications, such as preventing organ dysfunction, the treatment of various neuropathies and polyneuropathies, and use as an antioxidant. Thioctic acid has been primarily administered by two methods in the prior art.
First, it has been administered via intravenous (IV) therapy. In IV therapy, a solution containing thioctic acid is delivered through an IV needle directly to a patient's blood stream. This method shows the benefits of a high absorption rate and high plasma levels.
IV therapy becomes problematic, however, when the therapy is designed for use in the long-term care of a patient. In order to utilize IV therapy as a delivery system, the IV must be administered by a medical professional. This typically requires the patient to visit a healthcare provider's office or hospital each time the thioctic acid is to be administered. The time required to visit the office frequently discourages the patient from continuing these visits. Thus, the patient will often discontinue treatment due to the inconvenience of making trips to the provider's office. The necessity for treatment through an office or hospital also creates a high cost for patients, insurance companies, and researchers who want to perform clinical trails. Furthermore, in the event that the patient continues treatment, frequent IV use may cause vein collapse and oxidative stress in the patient.
The second method typically utilizes an orally administered, GI delivery system using a tablet, powder, or soft-gel formulation of thioctic acid. This offers a method of administration which does not require a health care provider's oversight. However, tablets and powders of thioctic acid are difficult for the human body to absorb.
Refined thioctic acid is insoluble in water at normal pH and at the acid pH seen in the stomach, although it is soluble in fat solvents. The dl-form of thioctic acid is likewise insoluble in water and soluble in fat solvents, but it can form a water-soluble sodium salt that is aqueous in water solutions that exist at a pH of about 7.4. However, this sodium salt also has a poor solubility at acid pH.
Due to this solubilization problem, thioctic acid taken in tablet and powder forms is almost entirely dependent upon bile salts in the small intestine for dispersal, which results in a slow absorption rate and low systemic plasma levels. Once bile salt dispersal of thioctic acid crystals has occurred, thioctic acid can penetrate epithelium in the manner of fat-soluble drugs, as well as utilize absorption mechanisms in the small intestine specific to medium chain fatty acids. Soft-gel variations of solubilized thioctic acid, and oral solutions, have been developed to speed up the dispersal process. However, for the most part these solutions are prone to polymerization and degradation reactions and are unstable during long term storage. More significantly, all previous oral delivery systems (including soft-gels and oral solutions) utilize the stomach and gastrointestinal (GI) tract for absorption.
Since the liver is the major organ implicated in the removal of thioctic acid from plasma, with a removal rate nearly equal to that of the clearance of plasma through the liver, slow GI absorption rates result in low systemic plasma levels due to the necessary passage of ingested substances through the hepatic portal vein of the liver (the first pass mechanism).
Due to the insoluble nature of thioctic acid and/or the liver's function to remove it from both systemically circulating plasma and the first pass mechanism of the hepatic portal vein, oral delivery systems that utilize the stomach and small intestine for absorption necessarily equate to relatively low absorption profiles, such that only a small percent of a given dose actually becomes utilized by the body. Therefore, a large degree of waste occurs when GI absorption mechanisms are utilized, and thus maximal benefits from thioctic acid supplementation are not achieved through GI absorption mechanisms.
Previous attempts to overcome the low absorption profiles of oral thioctic acid doses have produced their own problems and side-effects. When high concentrations of thioctic acid make continued contact with cells in the mouth and GI tract (including the stomach), those cells may swell and burst, causing an apoptotic “burn” effect. This apoptotic effect is what caused lethality in animals utilized for LD50 studies, where said animals died from liver failure. Upon histological examination, liver mitochondria of said animals were seen to have burst due to an osmotic imbalance as thioctic acid flooded into these cells. As such, due to this osmotic/apoptotic effect current formulations of a swallowed tablet, powder, or soft-gel can be uncomfortable or harmful to the patient, particularly when taken in high enough doses to produce IV equivalent plasma levels.
A solution is needed to address one or more of these shortcomings in the prior art.